Pancreatic islet transplantation is less efficient than whole organ pancreas transplantation in reversing the hyperglycemia of diabetes. One of the major reasons for this disparity may be the loss of islets to ischemic injury during the time it takes for the islets to revascularize in the recipient. On this basis, we have prepared composite "islet kidneys" (IK) by transplantation of autologous islets under the kidney capsule 2-3 months prior to transplantation of the composite organ into pancreatectomized miniature swine. Transplantation of IKs was found to restore euglycemia to pancreatectomized recipients immediately, and to maintain both renal and islet functions long-term. Our data also indicate that a single living donor pancreas contains sufficient islets to support the long-term insulin requirements of both the donor and recipient of such a prevascularized IK. The goals of this R33 proposal are: 1) to understand of the mechanism by which IK provide this marked advantage over free islets in swine; and 2) to extend these studies to in vivo functional studies of IK in non-human primates as a preclinical model for treatment of diabetic patients with end-stage renal disease. Specifically, we will: 1) Analyze the factors responsible for the advantage of vascularized IK over free islet transplants in achieving successful islet function; 2) Utilize the genetics of the miniature swine model to determine the relative importance of MHC matching in achieving successful reversal of diabetes by IK grafts; 3) Establish an IK transplantation model in baboons and assess the ability of allogeneic IK transplantation to reverse hyperglycemia in diabetic baboons; and 4) Develop non-invasive techniques for partial pancreatectomy, preparation of IK and IK removal for transplantation. The research team assembled for this "bench-to-bedside" approach includes: 1) basic scientists in the Transplantation Biology Research Center, 2) clinicians at the Massachusetts General Hospital involved in transplantation and diabetes research, and 3) consultants with outstanding expertise related to the techniques to be developed. We anticipate that the use of pre-vascularized islets as part of a composite islet-kidney transplant may provide a new and effective treatment modality for patients with class I diabetes and end-stage renal disease.